Alpha-Galactosidase A Protein

Alpha-Galactosidase A Protein

Introduction

Alpha Galactosidase A Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein"> [@schiffmann2009]

| Attribute | Value | [@eng2007]
|-----------|-------| [@waldek2013]
| Protein Name | Alpha-Galactosidase A |
| Gene Symbol | GLA |
| UniProt ID | P06280 |
| PDB Structures | 2VLW, 4AKH, 1R46, 5FEB |
| Molecular Weight | 50.7 kDa (dimer: 101.4 kDa) |
| Subcellular Localization | Lysosome |
| Protein Family | Glycoside hydrolase family 27 |

</div>}

Overview

Alpha-Galactosidase A (α-Gal A) is a lysosomal hydrolase that catalyzes the hydrolysis of globotriaosylceramide (GL-3) and other glycolipids with terminal alpha-galactosyl residues.^[1] Deficiency causes Fabry disease, an X-linked lysosomal storage disorder. Enzyme replacement therapy is available for treatment.

Structure

Quaternary Structure

• Primary structure: 429 amino acids (including signal peptide)
• Processed form: 398 amino acids (after signal peptide removal)
• Quaternary: Homodimer
• Glycosylation: N-linked glycans at positions 108, 146, 192

Active Site

• Catalytic residues: Asp170, Asp231 (acid/base catalysts)
• Substrate binding: Hydrophobic pocket for globotriaosylceramide
• Specificity: Terminal α-galactosyl residues

PDB Structures

Alpha-Galactosidase A Protein

Introduction

Alpha Galactosidase A Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein"> [@schiffmann2009]

| Attribute | Value | [@eng2007]
|-----------|-------| [@waldek2013]
| Protein Name | Alpha-Galactosidase A |
| Gene Symbol | GLA |
| UniProt ID | P06280 |
| PDB Structures | 2VLW, 4AKH, 1R46, 5FEB |
| Molecular Weight | 50.7 kDa (dimer: 101.4 kDa) |
| Subcellular Localization | Lysosome |
| Protein Family | Glycoside hydrolase family 27 |

</div>}

Overview

Alpha-Galactosidase A (α-Gal A) is a lysosomal hydrolase that catalyzes the hydrolysis of globotriaosylceramide (GL-3) and other glycolipids with terminal alpha-galactosyl residues.^[1] Deficiency causes Fabry disease, an X-linked lysosomal storage disorder. Enzyme replacement therapy is available for treatment.

Structure

Quaternary Structure

• Primary structure: 429 amino acids (including signal peptide)
• Processed form: 398 amino acids (after signal peptide removal)
• Quaternary: Homodimer
• Glycosylation: N-linked glycans at positions 108, 146, 192

Active Site

• Catalytic residues: Asp170, Asp231 (acid/base catalysts)
• Substrate binding: Hydrophobic pocket for globotriaosylceramide
• Specificity: Terminal α-galactosyl residues

PDB Structures

| PDB ID | Description | Resolution |
|--------|-------------|------------|
| 2VLW | Native enzyme | 2.6 Å |
| 1R46 | With inhibitor | 2.0 Å |
| 4AKH | Dimer interface | 2.4 Å |
| 5FEB | Fabry disease mutant | 2.3 Å |

Normal Function

Catalytic Mechanism

α-Gal A hydrolyzes terminal α-galactosyl residues:^[2]

Primary substrate: Globotriaosylceramide (GL-3, Gb3)
GL-3 (Ceramide-Glc-Gal-Gal) → Ceramide-Glc-Gal + Galactose

Other substrates:

• Digalactosylceramide (Gal-Gal-Cer)
• Galactose-α1,4-galactose oligosaccharides

Physiological Role

• Glycolipid catabolism: Prevents accumulation of GL-3
• Membrane turnover: Processes glycolipids from aging membranes
• Renal function: Critical for glomerular and tubular cells
• Vascular function: Prevents endothelial glycolipid accumulation

Role in Disease

Fabry Disease

Deficient α-Gal A activity causes Fabry disease:^[3]

Pathophysiology:

Clinical manifestations:

• Kidney: Proteinuria, renal failure
• Heart: LVH, cardiomyopathy, arrhythmias
• Brain: TIA/stroke, white matter lesions
• Peripheral nerves: Pain crises, autonomic dysfunction

Enzyme Activity Levels

| Activity (%) | Phenotype |
|--------------|-----------|
| <1% | Classic Fabry |
| 1-30% | Late-onset/ variant |
| >30% | Carrier (usually mild) |

Therapeutic Targeting

Two FDA-approved enzyme replacement therapies:^[4]

| Treatment | Dose | Route |
|-----------|------|-------|
| Agalsidase alpha | 0.2 mg/kg | IV every 2 weeks |
| Agalsidase beta | 1.0 mg/kg | IV every 2 weeks |
| Migalastat | 123 mg | Oral (if amenable) |

Mechanism:

• ERT: Recombinant enzyme taken up via mannose-6-phosphate receptors
• Chaperone: Migalastat stabilizes mutant enzyme, increases residual activity

Key Publications

Background

The study of Alpha Galactosidase A Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[@germain2010]: Germain DP. "Fabry disease." Orphanet J Rare Dis. 2010;5:30. PMID: 21146940(https://pubmed.ncbi.nlm.nih.gov/21146940/)
[@schiffmann2009]: Schiffmann R, et al. "Enzyme replacement therapy in Fabry disease: A randomized controlled trial." JAMA. 2009;301(11):1137-1145. PMID: 19318652(https://pubmed.ncbi.nlm.nih.gov/19318652/)
[@eng2007]: Eng CM, et al. "Safety and efficacy of agalsidase alfa in Fabry disease." Genet Med. 2007;9(9):605-612. PMID: 17873679(https://pubmed.ncbi.nlm.nih.gov/17873679/)
[@waldek2013]: Waldek S, et al. "Agalsidase beta therapy for Fabry disease: 10-year experience." Mol Genet Metab. 2013;108(4):253-264. PMID: 23419421(https://pubmed.ncbi.nlm.nih.gov/23419421/)

See Also

• [Fabry Disease](/diseases/fabry-disease)
• [Lysosomal Storage Disorders](/diseases/lysosomal-storage-disorders)
• Glycolipid Metabolism
• [Enzyme Replacement Therapy](/therapeutics/enzyme-replacement-therapy)